Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine

A.J. Black, Howard McLeod, HA Capell, RH Powrie, LK Matowe, Stuart C Pritchard, Elaina Susan Renata Collie-Duguid, David M Reid

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Abstract

Background: Substantial hematologic toxicity limits the use of azathioprine.

Objective: To evaluate 1) polymorphic inactivation of azathioprine by thiopurine methyltransferase and 2) clinical toxicity.

Design: Prospective cohort study.

Setting: Two rheumatology units.

Patients: 67 patients for whom azathioprine was prescribed as second-line therapy for rheumatic disease.

Measurements: Polymerase chain reaction-based assays were used to detect mutations in thiopurine methyltransferase. The primary end point was discontinuation of azathioprine therapy because of toxicity.

Results: Six of 67 patients (9%) were heterozygous for mutant thiopurine methyltransferase alleles. Five of the 6 patients discontinued therapy within 1 month of starting treatment because of low leukocyte counts. The sixth patient did not adhere to treatment. Patients with wild-type thiopurine methyltransferase alleles received therapy longer than did patients with mutant alleles (median duration of therapy, 39 weeks [range, 6 to 180 weeks] and 2 weeks [range, 2 to 4 weeks], respectively; P = 0.018).

Conclusion: Analysis of thiopurine methyltransferase genotype is a quick way to identify patients at risk for acute toxicity from azathioprine.

Original languageEnglish
Pages (from-to)716-718
Number of pages3
JournalAnnals of Internal Medicine
Volume129
Issue number9
Publication statusPublished - 1 Nov 1998

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thiopurine methyltransferase
Azathioprine
Genotype
Alleles
Therapeutics
Rheumatology
Rheumatic Diseases
Leukocyte Count

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Black, A. J., McLeod, H., Capell, HA., Powrie, RH., Matowe, LK., Pritchard, S. C., ... Reid, D. M. (1998). Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine. Annals of Internal Medicine, 129(9), 716-718.

Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine. / Black, A.J.; McLeod, Howard; Capell, HA; Powrie, RH; Matowe, LK; Pritchard, Stuart C; Collie-Duguid, Elaina Susan Renata; Reid, David M.

In: Annals of Internal Medicine, Vol. 129, No. 9, 01.11.1998, p. 716-718.

Research output: Contribution to journalArticle

Black, AJ, McLeod, H, Capell, HA, Powrie, RH, Matowe, LK, Pritchard, SC, Collie-Duguid, ESR & Reid, DM 1998, 'Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine' Annals of Internal Medicine, vol. 129, no. 9, pp. 716-718.
Black AJ, McLeod H, Capell HA, Powrie RH, Matowe LK, Pritchard SC et al. Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine. Annals of Internal Medicine. 1998 Nov 1;129(9):716-718.
Black, A.J. ; McLeod, Howard ; Capell, HA ; Powrie, RH ; Matowe, LK ; Pritchard, Stuart C ; Collie-Duguid, Elaina Susan Renata ; Reid, David M. / Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine. In: Annals of Internal Medicine. 1998 ; Vol. 129, No. 9. pp. 716-718.
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abstract = "Background: Substantial hematologic toxicity limits the use of azathioprine. Objective: To evaluate 1) polymorphic inactivation of azathioprine by thiopurine methyltransferase and 2) clinical toxicity. Design: Prospective cohort study. Setting: Two rheumatology units. Patients: 67 patients for whom azathioprine was prescribed as second-line therapy for rheumatic disease. Measurements: Polymerase chain reaction-based assays were used to detect mutations in thiopurine methyltransferase. The primary end point was discontinuation of azathioprine therapy because of toxicity. Results: Six of 67 patients (9{\%}) were heterozygous for mutant thiopurine methyltransferase alleles. Five of the 6 patients discontinued therapy within 1 month of starting treatment because of low leukocyte counts. The sixth patient did not adhere to treatment. Patients with wild-type thiopurine methyltransferase alleles received therapy longer than did patients with mutant alleles (median duration of therapy, 39 weeks [range, 6 to 180 weeks] and 2 weeks [range, 2 to 4 weeks], respectively; P = 0.018). Conclusion: Analysis of thiopurine methyltransferase genotype is a quick way to identify patients at risk for acute toxicity from azathioprine.",
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N2 - Background: Substantial hematologic toxicity limits the use of azathioprine. Objective: To evaluate 1) polymorphic inactivation of azathioprine by thiopurine methyltransferase and 2) clinical toxicity. Design: Prospective cohort study. Setting: Two rheumatology units. Patients: 67 patients for whom azathioprine was prescribed as second-line therapy for rheumatic disease. Measurements: Polymerase chain reaction-based assays were used to detect mutations in thiopurine methyltransferase. The primary end point was discontinuation of azathioprine therapy because of toxicity. Results: Six of 67 patients (9%) were heterozygous for mutant thiopurine methyltransferase alleles. Five of the 6 patients discontinued therapy within 1 month of starting treatment because of low leukocyte counts. The sixth patient did not adhere to treatment. Patients with wild-type thiopurine methyltransferase alleles received therapy longer than did patients with mutant alleles (median duration of therapy, 39 weeks [range, 6 to 180 weeks] and 2 weeks [range, 2 to 4 weeks], respectively; P = 0.018). Conclusion: Analysis of thiopurine methyltransferase genotype is a quick way to identify patients at risk for acute toxicity from azathioprine.

AB - Background: Substantial hematologic toxicity limits the use of azathioprine. Objective: To evaluate 1) polymorphic inactivation of azathioprine by thiopurine methyltransferase and 2) clinical toxicity. Design: Prospective cohort study. Setting: Two rheumatology units. Patients: 67 patients for whom azathioprine was prescribed as second-line therapy for rheumatic disease. Measurements: Polymerase chain reaction-based assays were used to detect mutations in thiopurine methyltransferase. The primary end point was discontinuation of azathioprine therapy because of toxicity. Results: Six of 67 patients (9%) were heterozygous for mutant thiopurine methyltransferase alleles. Five of the 6 patients discontinued therapy within 1 month of starting treatment because of low leukocyte counts. The sixth patient did not adhere to treatment. Patients with wild-type thiopurine methyltransferase alleles received therapy longer than did patients with mutant alleles (median duration of therapy, 39 weeks [range, 6 to 180 weeks] and 2 weeks [range, 2 to 4 weeks], respectively; P = 0.018). Conclusion: Analysis of thiopurine methyltransferase genotype is a quick way to identify patients at risk for acute toxicity from azathioprine.

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